Methods of Assessing Risk of Developing Prostate Cancer

The present disclosure relates to methods and systems for assessing the risk of a human male subject for developing prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in men, excluding melanoma, (Rawla, 2019) with current screening options including digital rectal examination and the prostate-specific antigen (PSA) test. PSA is an important biomarker, and while PSA screening has drastically reduced the incidence of late-stage metastatic prostate cancer, it has also caused an increase in indolent tumour detection. Men with indolent prostate cancers would likely die from a cause other than prostate cancer (Jahn et al., 2015). Thus, detection of these tumours is considered over-diagnosis. To put this into context, the lifetime risk of developing prostate cancer is approximately 13.5%, whereas the risk of dying from prostate cancer is approximately 2.5% (Barry and Simmons, 2017). Optimising prostate cancer screening by enabling detection of aggressive cancer while avoiding over-diagnosis is an important clinical objective.

Risk assessment may enable identification of men who are at substantially increased risk of developing prostate cancer. A variety of risk assessment tools are currently used in the prostate cancer space; however, most of these are used after screening to help in decision-making regarding biopsy or treatment. Few of these tools are used before screening where there is an opportunity to focus screening strategies to only include those men who are at increased risk. Such an approach has the potential to reduce over-diagnosis of prostate cancer and subsequent over-treatment (Pereira-Azevedo et al., 2017).

Because of the challenges related to over-diagnosis, routine PSA screening is a controversial subject in the international medical community. In the United States, PSA screening is recommended starting at age 50-55 years, but can begin as early as age 40 years based on clinician recommendation for high-risk men; screening frequency depends on PSA level (American Cancer Society, 2022; Fenton et al., 2018). In the United Kingdom and Australia, there is an informed choice program instead of a national PSA screening program; any man aged 50 years or older can choose to have his PSA level tested, but can begin as early as age 40 based on family history of disease (National Health Service, 2022; Public Health England, 2022; Cabarkapa et al., 2016). High risk of prostate cancer is currently determined by age, family history and ethnicity. But, there are other factors that influence risk.

Family history is a widely accepted risk factor for prostate cancer. Familial risk is strong, representing a 2- to 3-fold increased risk based on a first-degree family history of prostate cancer (Brandão et al., 2020). Some of the familial risk can be explained by high-penetrance genetic variants such as mutations in the BRCA1 and BRCA2 genes (Pilie et al., 2016). However, like with many cancers, this high-penetrance genetic susceptibility represents less than 20% of all prostate cancer cases (Brandão et al., 2020). Interestingly, there remains a genetic susceptibility in the form of low-penetrance single-nucleotide polymorphisms (SNPs) that explain a portion of risk and are largely independent of familial history risk (Conti et al., 2021). This genetic susceptibility component is known as polygenic risk.

Despite available tools, there is a need for further prostate cancer risk assessment methods.

The present inventors have identified improved methods of assessing the risk of a human male subject for developing prostate cancer.

In one aspect, the present invention provides a method for assessing the risk of a human male subject for developing prostate cancer comprising:

In an embodiment, the genetic risk assessment comprises detecting the presence of at least one, at least two, at least five, at least 10, at least 25, at least 50, at least 100, at least 150, at least 200, or at least 250 of the polymorphisms selected from any one of Tables 1 to 4, or a polymorphism in linkage disequilibrium with one or more thereof.

In an embodiment, the genetic risk assessment comprises detecting the presence of each of the polymorphisms provided in Table 1, Table 2, Table 3 or Table 4, or a polymorphism in linkage disequilibrium with one or more thereof.

In an embodiment, performing the clinical risk assessment involves obtaining information from the subject on one or more of the following: age, ethnicity, family history of prostate cancer incorporating number of first-degree relatives who have had prostate cancer, the age of the youngest first-degree relative at diagnosis with prostate cancer, the number of second-degree relatives who have had prostate cancer, country of residence or protein marker levels.

In an embodiment, performing the clinical risk assessment comprises, or consists of, obtaining information from the subject on age and first-degree relative history of prostate cancer.

In an embodiment, the subject is at least 40 years old. In an embodiment, the subject is between 40 and 69 years old.

In an embodiment, the results of the risk assessment indicate that the subject should be enrolled in a screening program or subjected to more frequent screening.

In an embodiment, the polymorphism in linkage disequilibrium has linkage disequilibrium above 0.9. In an embodiment, the polymorphism in linkage disequilibrium has linkage disequilibrium of 1.

In an embodiment, the method further comprises comparing the risk to a pre-determined threshold.

In an embodiment, the genetic risk assessment produces a polygenic risk score (PRS).

In an embodiment, the polygenic risk score is determined using an odds ratio (OR) for each effect allele and effect allele frequency (p).

In an embodiment, for each polymorphism the unscaled population average risk (μ) is calculated as:

In an embodiment, an adjusted risk for each polymorphism is calculated as adjusted risk=(OR)/μ, where N is the number of effect alleles.

In an embodiment, the polygenic risk score is determined by combining the adjusted risk for each polymorphism.

In an embodiment, the adjusted risk for each polymorphism are combined by multiplication.

In an embodiment, the method comprises determining the natural logarithm of the PRS (lnPRS).

In an embodiment, lnPRS is multiplied by a predetermined β coefficient.

In an embodiment, the β coefficient is about 1.7 such as 1.766.

In an embodiment, the method comprises determining the relative risk (rrisk) of developing prostate cancer using;

In an embodiment, the age categories are 40 to 49, 50 to 59 and 60 to 69. In an embodiment,

In an embodiment, one or more or all of the following apply;

In an embodiment, one or more or all of the following apply;

In an alternate embodiment, the β coefficient is about 1.03 such as 1.0307.

In an alternate embodiment, the method comprises determining the relative risk (rrisk) of developing prostate cancer using;

In an embodiment, one or more or all of the following apply;

In an embodiment, one or more or all of the following apply;

In an embodiment, the method comprises determining one or more or all of the absolute 5-year risk, the absolute 10-year risk, or the absolute remaining lifetime risk (to age 90).

In another aspect, the present invention provides a computer-implemented method for assessing the risk of a human male subject for developing prostate cancer, the method operable in a computing system comprising a processor and a memory, the method comprising:

In an embodiment, the clinical risk data and genetic risk data for the subject is received from a user interface coupled to the computing system.

In an embodiment, the clinical risk data and genetic risk data for the subject is received from a remote device across a wireless communications network.

In an embodiment, outputting comprises outputting information to a user interface coupled to the computing system.

In an embodiment, the method comprises determining a genetic risk score based on genetic data derived from a biological sample taken from the male subject.

In an embodiment, the method comprises determining the relative risk (rrisk) of developing prostate cancer using;

In an alternate embodiment, the method comprises determining the relative risk (rrisk) of developing prostate cancer using;

In a further aspect, the present invention provides computer readable storage medium storing executable code, wherein when a processor executes the code, the processor is cause to perform a computer-implemented method of the invention.

Furthermore, provided is a device for assessing the risk of a human male subject developing prostate cancer, the device comprising:

In an embodiment, the device further comprises a display component, wherein the processor is further caused to display the prostate cancer risk score of the male subject for developing prostate cancer on the display component.

In an embodiment, the device further comprises a communications module, wherein the processor is further caused to communicate the prostate cancer risk score of the male subject for developing prostate cancer to an external device via the communications module.